MicroRNA expression profile of gastrointestinal stromal tumors is distinguished by 14q loss and anatomic site Hee-Jung Choi 1,2 , Hanna Lee 1,2 , Hyunki Kim 1 , Ji Eun Kwon 1,2 , Hyun Ju Kang 1,2 , Kwon Tae You 1,2 , Hwanseok Rhee 2 , Sung Hoon Noh 3 , Young-Ki Paik 4 , Woo Jin Hyung 3 and Hoguen Kim 1,2 1 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea 2 Brain Korea 21 Projects for Medical Sciences, Yonsei University College of Medicine, Seoul, Korea 3 Department of Surgery, Yonsei University College of Medicine, Seoul, Korea 4 Department of Biochemistry and Bioproducts Research Center, Yonsei Proteome Research Center, Yonsei University, Seoul, Korea MicroRNAs are known to regulate gene expression. Although unique microRNA expression profiles have been reported in several tumors, little is known about microRNA expression profiles in GISTs. To evaluate the relationship between microRNA expression and clinicopathologic findings of GISTs, we analyzed the microRNA expression profiles of GISTs. We used fresh frozen tissues from 20 GISTs and analyzed KIT and PDGFRA mutations and chromosomal loss status. MicroRNA expression was analyzed using a microRNA chip containing 470 microRNAs. Using unsupervised hierarchical clustering analysis, we found four distinct microRNA expression patterns in our 20 GISTs. Six GISTs that did not have 14q loss formed a separate cluster. In the 14 GISTs with 14q loss, 5 small bowel GISTs formed a separate cluster and the remaining 9 GISTs could be divided into two groups according to frequent chromosomal losses and tumor risk. We found 73 microRNAs that were significantly down- regulated in the GISTs with 14q loss; 38 of these microRNAs are encoded on 14q. We also found many microRNAs that were down-regulated in small bowel and high-risk group GISTs. Most of the microRNAs down-regulated in the high-risk group and small bowel GISTs are known to be involved in tumor progression, specifically by stimulating mitogen-activated protein kinase (MAPK) and the cell cycle. The microRNA expression patterns of GISTs are closely related to the status of 14q loss, anatomic site, and tumor risk. These findings suggest that microRNA expression patterns can differentiate several subsets of GISTs. The molecular features of gastrointestinal stromal tumors (GISTs) are among the best characterized of all human tumors. 1–4 Activating mutations of the v-kit Hardy-Zucker- man 4 feline sarcoma viral oncogene homolog (KIT), a mem- ber of the receptor tyrosine kinase III family, are the most common genetic events in GISTs. KIT mutations are known to be present in 80% of GISTs 5–7 and result in the auto- phosphorylation of KIT, resulting in activation of down- stream signaling pathways. 8–10 Gain-of-function mutations of platelet-derived growth factor receptor a (PDGFRA), another member of the receptor tyrosine kinase III family, are present in 35% of GISTs that lack KIT mutations. 11 Activating mutations of KIT and PDGFRA are mutually exclusive, and mutations in PDGFRA are regarded as an alternative onco- genic mechanism in GISTs. 11,12 The characteristic fragile genomic sites of GISTs are well- known. The most common and characteristic genomic change is the loss of the long arm of chromosome 14 (14q). 13,14 The other well-known chromosomal alterations are deletions of chromosome 1p and 22q. 15–19 Loss of 14q is known to be present in 70% of GISTs, has no relationship to tumor risk, and can be found in any type of GIST. 16,20 The other chromosomal changes are relatively infrequent, but occur more frequently in high-risk GISTs. 15,16,21 Although certain molecular changes are characteristic of GISTs, few of these molecular characteristics explain the bio- logic behavior of the tumor or are useful for molecular classi- fication. In previous studies, we demonstrated that the gene expression profiles of GISTs are relatively homogeneous and have some relationship to the absence or presence of 14q and KIT mutations. 12,22 We could not, however, find any other relationship between the gene expression profile and biologi- cal behavior of GISTs. The microRNA expression profiles of GISTs have been compared to other types of sarcomas. 23 However, the microRNA expression characteristics of subsets of GISTs and their relationship to genetic and clinicopatho- logic factors are unknown. It has been reported that micro- RNA expression is related to tumorigenesis and the Key words: microRNA, gastrointestinal stromal tumors, KIT, loss of 14q Additional Supporting Information may be found in the online version of this article Grant sponsor: Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea; Grant number: A030003; Grant sponsor: 21C Frontier Functional Proteomics Project, Korean Ministry of Education, Science and Technology; Grant number: FPR08A2-100 DOI: 10.1002/ijc.24897 History: Received 8 Feb 2009; Accepted 4 Sep 2009; Online 30 Sep 2009 Correspondence to: Hoguen Kim, Department of Pathology, Yonsei University College of Medicine, CPO Box 8044, Seoul, Korea, Fax: þ82-2-363-5263, E-mail: hkyonsei@yuhs.ac Cancer Genetics Int. J. Cancer: 126, 1640–1650 (2010) V C 2009 UICC International Journal of Cancer IJC